Irinotecan and Temozolomide in Combination With Existing High Dose Alkylator Based Chemotherapy for Treatment of Patients With Newly Diagnosed Ewing Sarcoma

A Phase II Trial of Irinotecan and Temozolomide in Combination With Existing High Dose Alkylator Based Chemotherapy for Treatment of Patients With Newly Diagnosed Ewing Sarcoma

The purpose of this study is to find out what effects, good and/or bad, the combination of irinotecan and temozolomide has on Ewing sarcoma.

Irinotecan and temozolomide are chemotherapy drugs that are used very often to treat pediatric patients at MSKCC. The investigators have used these two drugs for many years to treat patients with Ewing sarcoma whose cancer has relapsed.

For patients with newly diagnosed Ewing sarcoma the current standard of care at MSKCC is a five drug chemotherapy regimen in combination with surgery and/or radiation therapy. This standard regimen is called the EFT regimen. . Some patients with Ewing sarcoma do not have their cancer cured by the chemotherapy and surgery/radiation therapy.

This study adds the chemotherapy drugs called irinotecan and temozolomide to the standard EFT regimen. The investigators are trying to improve the success of standard therapy by adding these drugs. The use of irinotecan and temozolomide in this study is experimental because they have not been used before in patients with newly diagnosed Ewing sarcoma. However the investigators have found these drugs to be effective in patients with relapsed Ewing sarcoma. It is not known if adding these two drugs will improve the outcomes of patients treated for Ewing sarcoma.

Study Overview

• Status: Recruiting
• Conditions: Newly Diagnosed Ewing Sarcoma
• Intervention / Treatment: Drug: Temozolomide; Drug: Cyclophosphamide; Drug: Vincristine; Procedure: Surgery; Drug: Irinotecan; Drug: Ifosfamide; Device: Doxorubicin; Drug: Etoposide; Radiation: Radiation Therapy*; Drug: Mesna; Drug: Dexrazoxane; Drug: G-CSF

• Study Type: Interventional
• Enrollment (Estimated): 93
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Paul Meyers, MD; Phone Number: 212-639-5952
• Study Contact Backup: Name: Emily Slotkin, MD; Phone Number: 212-639-8856

Study Locations

• United States
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Contact: Emily Slotkin, MD; Phone Number: 212-639-8856
    • Middletown, New Jersey, United States, 07748
      • Recruiting
      • Memorial Sloan Kettering Monmouth
      • Contact: Emily MD, MD; Phone Number: 212-639-8856
    • Montvale, New Jersey, United States, 07645
      • Recruiting
      • Memorial Sloan Kettering Bergen
      • Contact: Emily Slotkin, MD; Phone Number: 212-639-8856
  • New York
    • Commack, New York, United States, 11725
      • Recruiting
      • Memorial Sloan Kettering Commack
      • Contact: Emily Slotkin, MD; Phone Number: 212-639-8856
    • Harrison, New York, United States, 10604
      • Recruiting
      • Memorial Sloan Kettering Westchester
      • Contact: Emily Slotkin, MD; Phone Number: 212-639-8856
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
      • Contact: Emily Slotkin, MD; Phone Number: 212-639-8856
    • Uniondale, New York, United States, 11553
      • Recruiting
      • Memorial Sloan Kettering Nassau
      • Contact: Emily Slotkin, MD; Phone Number: 212-639-8856

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 40 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age greater than or equal to one year and less than or equal to 40 years at the time of diagnosis
• Newly diagnosed, previously untreated patients with histologically or molecularly confirmed Ewing sarcoma
• Adequate hematologic function:
• Absolute neutrophil count ≥ 1,000/K/mcl
• Platelet count ≥ 100,000/Kmcl
• Adequate renal function:
• Normal creatinine for age (See table below) OR
• Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 Age(Years) Maximum Serum Creatinine (mg/dL) ≤ 5 0.8 6 to ≤ 10 1 11 to ≤ 15 1.2 ≥ 16 1.5

Adequate hepatic function:

• Total bilirubin ≤ 1.5 x the ULN
• AST ≤ 2.5 x the ULN [in the absence of hepatic involvement of tumor. Patients with hepatic involvement are considered eligibile for study]
• ALT ≤ 2.5 x the ULN [in the absence of hepatic involvement of tumor. Patients with hepatic involvement are considered eligibile for study]

Normal cardiac function:

• Shortening fraction ≥ 28% by echocardiogram OR
• Left ventricular ejection fraction (LVEF) ≥ 50% on technetium- 99m pertechnetate radionuclide cineangiography (MUGA) or echocardiogram
• Patients must consent to an indwelling central venous catheter.
• Sexually active patients of reproductive potential must be willing to use an effective method of contraception.

Exclusion Criteria:

• Prior chemotherapy or radiotherapy (other than limited, emergent radiotherapy for treatment of eg. spinal cord compromise or threatened airway)
• Pregnant or breastfeeding females

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patients with localized disease; Patients with localized disease will receive six cycles of the combination as "maintenance" therapy following standard chemotherapy.; Cycles 4-6 will include:Ifosfamide 2,800 mg/m2/day on days 1-5Etoposide 100 mg/m2/day on days 1-5; Cycle 7 will include :Cyclophosphamide will be given on days 1 and 2 at a dose of 2,100 mg/m2/day, or for patients < 10 years of age at a dose of 70 mg/kg/dayDoxorubicin will be given on days 1 and 2 at a dose of 37.5 mg/m2/dayVincristine will be given on day 1 at a dose of 2 mg/m2 or 0.067 mg/kg (whichever is lower, to a max dose of 2 mg); Cycles 8-13 will include:Irinotecan will be given on 10 days over weeks 1 and 2 of a cycle at a dose of 20 mg/m2/day intravenouslyTemozolomide will be given daily on the first 5 days of irinotecan administration at a dose of 100 mg/m2/day orally or intravenously	Drug: Temozolomide; Drug: Cyclophosphamide; Drug: Vincristine; Procedure: Surgery; Drug: Irinotecan; Drug: Ifosfamide; Device: Doxorubicin; Drug: Etoposide; Radiation: Radiation Therapy*; If local control includes RT, RT should be given concurrently with chemotherapy cycles; Drug: Mesna; Mesna 2,100 mg/m2 (or 70 mg/kg if < 10 yrs of age) administered intravenously in concordance with institutional pediatric administration guidelines.; Drug: Dexrazoxane; Dexrazoxane 375 mg/m2 intravenously over approximately 15-30 minutes and as clinically indicated. To be administered immediately prior to doxorubicin.; Drug: G-CSF; G-CSF-to be administered after the completion of appropriate chemotherapy cycles as per institutional guidelines.
Experimental: Patients with metastatic disease; Patients will get 10 cycles of the combination intercalated between the final 4 cycles of standard chemotherapy.; Cycles 4, 5, 7, 8, 10, 11, 13, 14, 16, and 17 will include:Irinotecan will be given on 10 days over weeks 1 and 2 of a cycle at a dose of 20 mg/m2/day intravenouslyTemozolomide will be given daily on the first 5 days of irinotecan administration at a dose of 100 mg/m2/day orally or intravenously; Cycles 6, 9, and 12 will include:Ifosfamide 2,800 mg/m2/day on days 1-5Etoposide 100 mg/m2/day on days 1-5; Cycle 15 will include:Cyclophosphamide will be given on days 1 and 2 at a dose of 2,100 mg/m2/day, or for patients < 10 years of age at a dose of 70 mg/kg/dayDoxorubicin will be given on days 1 and 2 at a dose of 37.5 mg/m2/dayVincristine will be given on day 1 at a dose of 2 mg/m2 or 0.067 mg/kg (whichever is lower, to a max dose of 2 mg)	Drug: Temozolomide; Drug: Cyclophosphamide; Drug: Vincristine; Procedure: Surgery; Drug: Irinotecan; Drug: Ifosfamide; Device: Doxorubicin; Drug: Etoposide; Radiation: Radiation Therapy*; If local control includes RT, RT should be given concurrently with chemotherapy cycles; Drug: Mesna; Mesna 2,100 mg/m2 (or 70 mg/kg if < 10 yrs of age) administered intravenously in concordance with institutional pediatric administration guidelines.; Drug: Dexrazoxane; Dexrazoxane 375 mg/m2 intravenously over approximately 15-30 minutes and as clinically indicated. To be administered immediately prior to doxorubicin.; Drug: G-CSF; G-CSF-to be administered after the completion of appropriate chemotherapy cycles as per institutional guidelines.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
event free survival of patients with localized disease	We will determine event free survival from the time of study entry for all patients. An event would include death from any cause, progression of tumor, recurrence of tumor, or second malignancy. Progressive disease (PD) will be defined according to RECIST 1.1.	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
event free survival of patients with metastatic disease	We will determine event free survival from the time of study entry for all patients. An event would include death from any cause, progression of tumor, recurrence of tumor, or second malignancy. Progressive disease (PD) will be defined according to RECIST 1.1.	4 years
adverse event profile	Toxicities are graded by the Common Toxicity Criteria (Version 4.0) developed by the National Cancer Institute (NCI) of the USA.	2 years

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Investigators: Principal Investigator: Emily Slotkin, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

Helpful Links

• Memorial Sloan-Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: May 23, 2013
• First Submitted That Met QC Criteria: May 28, 2013
• First Posted (Estimated): May 29, 2013

Study Record Updates

• Last Update Posted (Actual): September 18, 2023
• Last Update Submitted That Met QC Criteria: September 15, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: CYCLOPHOSPHAMIDE (CYTOXAN); DOXORUBICIN/ADRIAMYCIN; ETOPOSIDE (VP-16); IFOSFAMIDE; IRINOTECAN (CPT-11) CAMPTOSAR; TEMOZOLOMIDE; VINCRISTINE; 13-068
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Sarcoma, Ewing; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cardiotonic Agents; Antibiotics, Antineoplastic; Topoisomerase I Inhibitors; Cyclophosphamide; Etoposide; Temozolomide; Ifosfamide; Irinotecan; Doxorubicin; Vincristine; Dexrazoxane; Razoxane
• Other Study ID Numbers: 13-068